Secondhand smoke (SHS) has significant detrimental cardiovascular effects, including sudden cardiac death and cardiac arrhythmias that kill more than any other disease. Reducing SHS exposure with smoking bans in public places has been shown to improve cardiovascular health in non-smokers. However, exposure to SHS continues to be a major public health concern. While there is no doubt that SHS exposure poses a significant cardiovascular health risk, the challenges are to resolve the causes and mechanisms. The objectives of this project are to systematically investigate 1) the concentration- and time-dependent changes in neuroplasticity of cardiac vagal neurons and cardiac electrical properties underlying SHS exposure-induced cardiovascular dysfunction; and 2) the contribution of inflammation, cardiac autonomic nervous system, and cardiac remodeling in SHS exposure-induced cardiovascular dysfunction. Aim 1 will determine concentration- and time-dependent SHS exposure-induced decreased heart rate variability (HRV) and increased arrhythmia burdens using telemetry ECG recordings in conscious mice and specialized data analysis software. Aim 2 will determine the extent to which reduced neuronal intrinsic excitability in anatomically identified cardiac vagal neurons in the nucleus ambiguous contributes to the SHS-induced concentration- and time-dependent changes in HRV using whole-cell patch-clamp technique in brainstem slices. Aim 3 will determine the extent to which direct remodeling of cardiac electrical properties contributes to the SHS-induced concentration- and time-dependent increase in arrhythmia susceptibility using optical imaging of electrophysiological properties in isolated hearts devoid of autonomic inputs. Aim 4 will determine the extent to which the inflammatory response and autonomic dysfunction contributes to the SHS-induced concentration- and time-dependent adverse effects. Three water soluble and orally available drugs will be tested: 1) epoxide hydrolase inhibitor, t- TUCB (trans-4-21-benzoic acid) that has been shown to attenuate SHS exposure-induced lung inflammation; 2) a commonly used ?1 blocker to block cardiac sympathetic activity; and 3) cardiac selective muscarinic (M2) blocker to block cardiac vagal activity. Establishing the concentration- and time-dependent effects of SHS may help to set regulatory policies on smoking exposure and focus public attention on risk assessment. Revealing the underlying mechanism(s) mediating SHS exposure-induced cardiovascular consequences will advance our scientific understanding of the causes of the adverse SHS-induced cardiovascular effects and may introduce new possibilities for novel therapeutic strategies.